Hypnotic activity of N3-benzylthymidine on mice

The pharmacological effect in mice of N3-benzylthymidine (N3-ByTd) was examined by two routes of administration; intravenous (i.v.) and intracerebroventricular (i.c.v.), and compared with the effect of administration of N3-benzyluridine (N3-ByUd) previously reported. Hypnotic activity, pentobarbital (PB)-induced sleeping time, motor incoordination and spontaneous activity were used as indices of pharmacological effects. N3-ByTd (0.5-2.0 mumol/mouse, i.c.v.) and N3-ByUd (1.5-3.0 mumol/mouse, i.c.v.) were found to possess dose-dependent hypnotic activity, and N3-ByTd had more potent hypnotic activity than N3-ByUd. Both N3-ByTd and N3-ByUd (0.5 and 1.0 mumol/mouse, i.c.v., respectively) showed a synergistic effect on PB-induced sleep, although their parent compounds, thymidine (Td) and uridine (Ud), did not potentiate the activity at each dose. In motor incoordination, the effect of N3-ByTd (0.5 mumol/mouse) continued for 6 hr after i.c.v. injection. All compounds decreased the spontaneous activity of mice by i.c.v. administration. Furthermore, both N3-ByTd and N3-ByUd decreased the activity, when they were administered by i.v. These results reveal that both N3-benzylpyrimidine nucleosides have more direct depressant effects on the central nervous system (CNS) than the parent compounds. Among the pyrimidine nucleoside derivatives tested, N3-ByTd was found to be the most potent hypnotic substance.